1. Field of the Invention
The present invention relates to the use of benzothiadiazide derivatives as nootropic agents (from the Greek "noo" to know) to treat: memory and learning disorders.
2. Description of Related Art
Heretofore, benzothiadiazide derivatives are known to exhibit diuretic and antihypertensive action.
The amino acid L-glutamate is the principal excitatory neurotransmitter in the mammalian CNS. This neurotransmitter exerts its effects by activating ionotropic and metabotropic receptors located on the dendrites and soma of neurons and glial cells.
The ionotropic glutamate receptors can be classified into three types according to their structure, conductance characteristics and selectivity for three synthetic agonists: NMDA (N-methyl-D-aspartic acid), AMPA (.alpha.-amino 2-3, dihydro-5-methyl-3-oxo-4-isoxazole propionic acid), and kainate (2-carboxy-4-(1-methylhexyl)-3-pyrrolidine aceticacid). A number of compounds that bind to these three types of ionotropic glutamate receptors have been demonstrated to facilitate or inhibit memory and learning processes in animals and humans. For example, ketamine, phencyclidine, and even more potently, dizocilpine (hereinafter "MK-801"), which are allosteric NMDA receptor antagonists, produce profound alterations in learning, disrupt memory consolidation and retrieval in animals and man, thereby eliciting a psychotic syndrome resembling schizophrenia in humans (1, 2, 3). On the other hand, aniracetam and related pyrrolidinone derivatives, by acting preferentially as positive allosteric modulators of AMPA receptor function (4,5), increase the strength of synaptic responses elicited by electrical stimulation of excitatory affferents to CAl hippocampal pyramidal neurons attenuating AMPA receptor spontaneous desensitization (6) and enhancing learning and memory (nootropic action) in animals (7,8,9).
Based on these observations and on the clinical evidence that several neurological diseases characterized by severe learning and memory loss (i.e., brain trauma, stroke, Alzheimer's disease and senile dementia) due to an impairment of glutamatergic transmission, the present inventors studied in detail the relationship existing between nootropic drug action and increase in excitatory amino acid synaptic strength using electrophysiological, behavioral, molecular biological and immunohistochemical techniques. A goal of the present study has been to search for nootropic drugs that increase synaptic strength of excitatory synapses by potently and selectively attenuating AMPA receptor desensitization. Aniracetam is a drug that decreases AMPA receptor desensitization, but due to its low potency and short lasting action, cannot be used efficaciously in therapy. Therefore, interest has focused on the development of potent derivatives of benzothiadiazide which, by allosterically reducing spontaneous AMPA receptor desensitization, increase excitatory synaptic strength in CAl hippocampal neurones, with a potency and duration of action that allows their use in therapy as nootropic drugs. It is also important that any such developed derivatives are able to cross the blood brain barrier in order to exert their therapeutic effect in the brain.